Cerebral amyloid angiopathy (CAA) is a common age related cerebral small vessel disease, characterised by progressive deposition of amyloid-β (Aβ), in particular Aβ40, in the wall of small to medium sized arteries, arterioles and capillaries of the cerebral cortex and overlying leptomeninges (Charidimou A et al., 2011). CAA often coexists with Alzheimer's disease (AD). Mild forms of CAA often appear asymptomatic; however, CAA may also lead to severe vascular pathologies and is a risk factor for cerebral hemorrhages ranging from silent microbleeds to spontaneous intracerebral haemorrhage, a devastating form of stroke.
APOE4 is a strong genetic risk factor for both AD and CAA (Shinohara M et al., 2016). Human ApoE is located on chromosome 19 (gene APOE, Uniprot P02649). Three major isoforms (apoE2, -3 and -4) are known in humans. ApoE4 (with Arg at positions 112 and 158) has an allele frequency of 5-35% in humans (Verghese P B et al., 2011) and ApoE4 homozygotes are estimated to represent about 2 to 3% of the general population (Quintino-Santos S R et al., 2012).
It has been shown that the ApoE4 allele is strongly associated with Aβ deposition in the cortical capillaries, so called capillary CAA (CAA-Type 1) (Thal et al., 2002). The second type of CAA (CAA-Type 2) presents Aβ deposition in leptomeningeal and cortical vessels, with the exception of cortical capillaries. CAA-type 2 is not associated with the ApoE4 allele.
Strategies that target decreasing Aβ by either: enhancing the amyloid clearance with an active or passive immunotherapy against Aβ; or decreasing production through inhibition of Beta-site-APP cleaving enzyme-1 (BACE-1, an enzyme involved in the processing of the amyloid precursor protein [APP]), may be of potential therapeutic value in the treatment of CAA. However, no effective disease-modifying treatment of CAA, nor the intracerebral haemorrhages associated therewith, has yet been described in the literature.
Beckmann N et al., 2016, describe the suitability of longitudinal noninvasive magnetic resonance imaging (MRI) in monitoring cerebral microhaemorrhages in vivo. In this study, the authors treated aged APP23 mice for three months with a potent BACE-inhibitor, NB360, and Aβ-antibody β1. In contrast to treatment with Aβ-antibody β1, volumetric MRI assessment revealed no effect on CAA-related microhaemorrhage in mice treated with NB360.